DESCRIPTION (Applicant's abstract): Autonomic neuropathy is a recognized complication of diabetes and can lead to dysfunction in the gastrointestinal, cardiovascular and urogenital systems. The overall objective of this study is to examine the hypothesis that oxidative stress plays a major role in the development of autonomic neuropathy in diabetes and that differences in anti-oxidant defense mechanisms in subpopulations of autonomic nerves can account for their relative susceptibility to diabetes-induced nerve damage. The study has been designed with the long-term objective of identifying specific targets for treatment and potential agents that may be beneficial clinically in preventing and reversing autonomic neuropathy. A multi-disciplinary approach, including microscopical, biochemical, molecular biological, pharmacological and electrophysiological techniques will be used to assess structure and function of a range of autonomic nerve types supplying the gastrointestinal tract. Studies will be carried out in an animal model of insulin-dependent (Type 1) diabetes mellitus and in isolated neurons in culture subjected to hyperglycemic conditions. Specific aims include investigation of apoptotic changes and the characterization of changes in indicators of oxidative stress, anti-oxidant defense mechanisms, heat shock protein 32 (induced by oxidative stress) and advanced glycation endproducts in subpopulations of autonomic nerves identified by their neurotransmitter content. Such changes will be correlated with the presence or absence of diabetes-induced damage in the same autonomic nerves. In addition, bimoclomol (an inducer of heat shock proteins) and aminoguanidine (an inhibitor of advanced glycation endproducts) will be examined in vivo and in vitro for their ability to prevent autonomic neuropathy and to reverse neuropathic changes once they have been allowed to develop.